Cancer, the uncontrolled growth of malignant cells, is a major health problem of the modern medical era and ranks second only to heart disease as a cause of death in the United States. Acute Myelogenous Leukemia (“AML”) is the most common acute leukemia in adults (Greer, J. P., et al. (2004) Wintrobe's Clinical Hematology, Baltimore pp. 2098-2142). Most patients who contract this disease succumb to it. Since the early seventies, the mainstay of therapy has been cytosine arabinoside (Ara-C) and anthracyclines (Greer, J. P., et al. (2004) Wintrobe's Clinical Hematology, Baltimore pp. 2098-2142). With the notable exception of all-trans retinoic acid for the treatment of acute promyelocytic leukemia, no new agent has had a major impact on disease outcome.
Stem cell transplantation has its limitations due to patients' age and availability of suitable donors. Furthermore, recent trials suggest that high dose therapy with stem cell rescue may not offer a survival advantage over standard dose chemotherapy (Cassileth, P. A., et al. (1998) New England Journal of Medicine 339(23): 1649-1656). Consequently, the need for new agents with new mechanisms of action for the treatment of AML and other types of cancer is evident.
Nitric oxide (NO) is a unique cytotoxic agent because of its multiple intracellular targets. As such, it constitutes an extremely potent antineoplastic agent. The main problem with NO has been the induction of hypotension by NO-generating compounds because of NO's pleotropic effects. It is known that NO is a major biologic effector molecule with functions in the vascular, immunologic and neurologic systems (Moncada, S., et al. (1991) Pharmacological Reviews 43:109-142). NO is produced in vivo by the nitric oxide synthases (NOS) (Moncada, S., et al. (1991) Pharmacological Reviews 43:109-142). For example, NO inhibits the growth of normal and malignant cells (Nathan, C. (1992) FASEB Journal 6:3051-3064). Additionally, NO inhibits growth and induces differentiation in AML cells (Magrinat, G., et al. (1992) Blood 80:1980-1986; Shami, P. J., et al. (1995) Leukemia Research 19; 527-533; Shami, P. J., et al. (1998) Leukemia 12: 1461-1466). A problem with widespread in vivo use of NO is its non-specific action on non-cancerous cells including its effects on vascular tissue resulting in hypotension.